This invention is directed generally to the inhibition of the binding of xcex14xcex21 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding, to pharmaceutically active compositions comprising such compounds and to the use of such compounds either as above, or in formulations for the control or prevention of disease states in which xcex14xcex21 is involved.
When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognize the invaded or damaged tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.
There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. The integrin xcex14xcex21 (also called VLA-4 for very late antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.
Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to xe2x80x9crollxe2x80x9d along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the xcex14xcex21 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.
Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1 and fibronectin.
Some of the diseases that might be treated by the inhibition of xcex14xcex21 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, and type I diabetes. In addition to being found on some white blood cells, xcex14xcex21 is also found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving xcex14xcex21 may be involved in the metastasis of certain cancers. Inhibitors of xcex14xcex21 binding may, therefore, also be useful in the treatment of some forms of cancer.
The isolation and purification of a peptide which inhibits the binding of xcex14xcex21 to a protein is disclosed in U.S. Pat. No. 5,510,332. Peptides which inhibit binding are disclosed in WO 95/15973, EP 0 341 915, EP 0 422 938 A1, U.S. Pat. No. 5,192,746 and WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247 and WO 98/04913.
It is therefore an object of the invention to provide novel compounds which are inhibitors of xcex14xcex21 binding, and pharmaceutical compositions including such novel compounds.
The invention is directed to novel compounds of Formula I as follows: 
wherein circle Q represents one or more rings;
q is an integer of zero to six;
M is selected from the group consisting of xe2x80x94C(R9)(R10)xe2x80x94 and xe2x80x94(CH2)uxe2x80x94, wherein u is an integer of from 0 to 3;
J is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR12xe2x80x94;
T is selected from the group consisting of xe2x80x94C(O)xe2x80x94 and xe2x80x94(CH2)bxe2x80x94 wherein b is an integer of from 0 to 3;
L is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NR13xe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94(CH2)vxe2x80x94 wherein v is an integer of 0 or 1;
X is selected from the group consisting of xe2x80x94CO2B, xe2x80x94PO3H2, xe2x80x94SO3H, xe2x80x94SO2NH2, xe2x80x94SO2NHCOR14, xe2x80x94OPO3H2, xe2x80x94C(O)NHC(O)R15, xe2x80x94C(O)NHSO2R16, tetrazolyl, oxazolyl and hydroxyl;
R11, R12 and R13 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, xe2x80x94CHxe2x95x90NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups; and,
B, R1, R4, R6, R8, R9, R10, R14, R15 and R16 at each occurrence are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)xe2x80x94NH(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C6 alkyl), xe2x80x94NHSO2(C1-C3 alkyl), xe2x80x94NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C1-C3)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)NHxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups;
wherein B, R1, R4, R6, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
wherein when L is xe2x80x94NR13xe2x80x94, R4 and R13 taken together may form a ring;
and wherein R6 and R8 taken together may form a ring;
and wherein when M is xe2x80x94C(R9)(R10)xe2x80x94, R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
For Formula I, presently preferred compounds may have circle Q as an aryl, cycloalkyl, biaryl or heterocyclyl ring.
More specifically, the compounds of this invention may be described by Formula II below 
wherein Y, at each occurrence, is independently selected from the group consisting of C(O), N, CR7, C(R2)(R3), NR5, CH, O and S;
m is an integer of from 2 to 5;
W is selected from the group consisting of C, N and CR22;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer of 0 to 3;
L is selected from the group consisting of O, NR13, S, and (CH2)n wherein n is an integer of 0 or 1;
R5, R11 and R13 at each occurrence, are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, xe2x80x94CHxe2x95x90NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups; and,
B, R2, R3, R4, R6, R7, R8, R9, R10 and R22 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)(C1-C3 alkyl), xe2x80x94NHC(O)N(CH1-C3 alkyl)C(O)xe2x80x94NH(C1-C3 alkyl), xe2x80x94NHC(O)NH(CH1-C6 alkyl), xe2x80x94NHSO2(C1-C3 alkyl), xe2x80x94NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C, xe2x80x94C3)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)NHxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups;
wherein B, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13 and R22 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and wherein when L is xe2x80x94NR13xe2x80x94, R4 and R13 taken together may form a ring; and wherein R6 and R8 taken together may form a ring; and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
More specifically, the compounds of this invention may be described by Formula III below 
wherein q is an integer of zero to four;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer of 0 to 3;
L is selected from the group consisting of O, NR13, S, and (CH2)n wherein n is an integer of 0 or 1;
R11 and R13 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, xe2x80x94CHxe2x95x90NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups; and,
B, R1, R4, R6, R8, R9 and R10 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkoxy, aliphatic acyl, xe2x80x94CF3,xe2x80x94CO2H, xe2x80x94SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C6 alkyl), xe2x80x94NHSO2(C1-C3 alkyl), xe2x80x94NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C1-C3)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)NH(C1-C3)alkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, haloalkyl, alkoxyalkoxy, carboxyaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups;
wherein B, R1, R4, R6, R8, R9, R10, R11 and R13 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and wherein when L is xe2x80x94NR13xe2x80x94, R4 and R13 taken together may form a ring;
and wherein R6 and R8 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Presently preferred compounds of Formula III have q as one or two; R1 at each occurrence independently as aralkyl or alkyl; R6 as alkyl; B, R8, R9, R10 and R11 ach independently as hydrogen, T as xe2x80x94(CH2)bxe2x80x94 wherein b is zero; L as xe2x80x94(CH2)nxe2x80x94 wherein n is zero and R4 as aryl.
More specifically, the compounds of this invention may be described by Formula IV below 
wherein s is an integer of zero to five;
R21 is selected from the group consisting of aryl, alkyheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino;
B, R6, R8, R9, R10, R17, R18, R19 and R20 at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkoxy, aliphatic acyl, xe2x80x94CF3, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94CN, NO2, xe2x80x94NH2, xe2x80x94OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C6 alkyl), xe2x80x94NHSO2(C1-C3 alkyl), xe2x80x94NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C1-C3)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3)alkyl, xe2x80x94C(O)NH(C1-C3)alkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, haloalkyl, alkoxyalkoxy, carboxyaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups; and,
R11 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, xe2x80x94CHxe2x95x90NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups;
wherein B, R6, R8, R9, R10, R11, R17, R18, R19, R20 and R21 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and wherein R6 and R8 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
and wherein R18 and R19 taken together may form a ring;
and wherein R19 and R20 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Presently preferred compounds of Formula IV have B, R8, R9, R10, R11, R18 and R20 each independently as hydrogen, R6 and R19 each independently as alkyl; s as an integer of zero to three; R17 at each occurrence independently as halogen, alkyl, haloalkyl, xe2x80x94CF3, alkoxy or xe2x80x94OH; and R21 as aryl. A presently most preferred compound of Formula IV has s as zero; R6 as butyl; B, R8, R9, R10, R11, R18 and R20 each independently as hydrogen; and R21 as 1,3-benzodioxol-5-yl.
Compounds of the present invention may also be described by Formula V, shown below. 
wherein circle Q is a ring selected from the group consisting of
q is an integer of zero to four; 
B, R1, R6, R8, R9 and R10 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94CO2H, xe2x80x94SH, xe2x80x94CN, NO2, xe2x80x94NH2, xe2x80x94OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94NHSO2(C1-C3 alkyl), xe2x80x94NHSO2(aryl), alkoxyalkyl, xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and xe2x80x94C(O)NH(benzyl);
R5 and R11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, xe2x80x94CHxe2x95x90NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and xe2x80x94C(O)NH(benzyl) groups; and,
R21 is selected from the group consisting of aryl, alkyheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino;
wherein B, R1, R5, R6, R8, R9, R10, R11 and R21 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and wherein R6 and R8 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Presently preferred compounds of Formula V have B, R6, R8, R9, R10 and R11 each independently as hydrogen and alkyl, R1 and R5, at each occurrence, independently as hydrogen, 2-thienylmethyl, benzyl or methyl and R21 as aryl.
Presently preferred compounds include (3S)-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-3-(2-thienylmethyl)tetrahydro-1(2H)-pyrimidinyl)hexanoyl)amino) propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2R,S)-2-(3-(3-chlorobenzyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2S)-2-(2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl)hexanoyl)amino) propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((2-(3-chlorophenyl)methyl)-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoyl)amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3,5-dimethoxyphenyl)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-fluoro-4-methoxyphenyl)propanoic acid, (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-({2-[3-(3-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-(3-isopropoxyphenyl)-3-({2-[3-(2-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3-ethoxy-4-methoxyphenyl)propanoic acid, (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4-methoxy-3-methylphenyl)propanoic acid, (3S)-3-{[2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-phenylpropanoic acid, (3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-({2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-phenylpropanoic acid, (3S)-3-(1-methyl-1H-indol-6-yl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid, (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-3-(2-naphthalenylmethyl)-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid, (3S)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)-3-[3-(2-methylpropyl)phenyl]propanoic acid, (3S)-3-[3-(difluoromethyl)phenyl]-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid, (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-3-[(2-methylphenyl)methyl]-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid, (3S)-3-(3-fluorophenyl)-3-({2-[5-methyl-2-oxo-3-(phenylmethyl)-1(2H)-pyridinyl]hexanoyl}amino)propanoic acid, (3S)-3-({2-[3-[(2-chloro-4-fluorophenyl)methyl]-5-methyl-2-oxo-1(2H)-pyridinyl]hexanoyl}amino)-3-{3-[(1-methylethyl)oxy]phenyl}propanoic acid and (3S)-3-{3-[(1-methylethyl)oxy]phenyl}-3-({2-[5-methyl-2-oxo-1-(phenylmethyl)-1,2-dihydro-3-pyridinyl]-2-phenylacetyl}amino) propanoic acid, and pharmaceutically acceptable salts thereof.
Other presently preferred compounds include (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(3xe2x80x2,4xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3xe2x80x2,4xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1xe2x80x2-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-(1,1xe2x80x2-biphenyl-4-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(4xe2x80x2-methyl-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4xe2x80x2-methyl-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4xe2x80x2-methyl-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2xe2x80x2,6xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2xe2x80x2,6xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2xe2x80x2,6xe2x80x2-dimethoxy-1,1xe2x80x2-biphenyl-4-yl)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-biphenyl-3-yl)propanoic acid, (3S)-3-(1,1xe2x80x2-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,1xe2x80x2-biphenyl-3-yl)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-{[(2S)-2-(3-benzyl-5-methyl-2-oxopyridin-1(2H)-yl)hexanoyl]amino}-3-(2xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-methylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(2xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-3-yl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dichlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2,6-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(3,5-dimethylbenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-fluoro-6-methoxybenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-(3,4-diethoxyphenyl)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chloro-6-fluorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]hexanoyl}amino)-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)propanoic acid, (3S)-3-({(2S)-2-[3-(2-chlorobenzyl)-5-methyl-2-oxopyridin-1(2H)-yl]-3-phenylpropanoyl}amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((2R)-2-(1-benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)hexanoyl)amino) propanoic acid and pharmaceutically acceptable salts thereof.
A presently most preferred compound is (3S)-3-(1,3-benzodioxol-5-yl)-3-((2S)-2-(3-benzyl-5-methyl-2-oxo-1(2H)-pyridinyl)hexanoylamino)propanoic acid or a pharmaceutically acceptable salt thereof.
Derivatives of Formulae I-V which are esters, carbamates, aminals, amides, optical isomers and pro-drugs are also contemplated.
The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.
The present invention further relates to a process of inhibiting the binding of xcex14xcex21 integrin to VCAM-1 comprising exposure of a cell expressing xcex14xcex21 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The xcex14xcex21 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses xcex14xcex21.
The invention also provides a method for treating disease states mediated by xcex14xcex21 binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.
The term xe2x80x9calkylxe2x80x9d as used herein, alone or in combination, refers to C1-C12 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a Cx-Cy designation. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
The term xe2x80x9calkenylxe2x80x9d as used herein, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.
The term xe2x80x9calkynylxe2x80x9d as used herein, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
The term xe2x80x9clowerxe2x80x9d modifying xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d refers to a C1-C6 unit for a particular functionality. For example lower alkyl means C1-C6 alkyl.
The term xe2x80x9caliphatic acylxe2x80x9d as used herein, alone or in combination, refers to radicals of formula alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94 and alkynyl-C(O)xe2x80x94 derived from an alkane-, alkene- or alkyncarboxylic acid, wherein the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl, among others.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
xe2x80x9cCycloalkylxe2x80x9d includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein alone or in combination refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkyl radical, including, but not limited to cyclohexylmethyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.
The term xe2x80x9calkoxyxe2x80x9d as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein, refers to Ryxe2x80x94Oxe2x80x94Rz, wherein Ry is lower alkyl as defined above, and Rz is alkylene (xe2x80x94(CH2)wxe2x80x94) wherein w is an integer of from one to six.
The term xe2x80x9calkenoxyxe2x80x9d as used herein, alone or in combination, refers to a radical of formula alkenyl-Oxe2x80x94, provided that the radical is not an enol ether, wherein the term xe2x80x9calkenylxe2x80x9d is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.
The term xe2x80x9calkynoxyxe2x80x9d as used herein, alone or in combination, refers to a radical of formula alkynyl-Oxe2x80x94, provided that the radical is not an -ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.
The term xe2x80x9cthioalkoxyxe2x80x9d refers to a thioether radical of formula alkyl-Sxe2x80x94, wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9csulfonamidoxe2x80x9d as used herein refers to xe2x80x94SO2NH2.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to xe2x80x94C(O)R wherein R is hydrogen.
The terms xe2x80x9ccarboxamidexe2x80x9d or xe2x80x9camidexe2x80x9d as used herein refer to xe2x80x94C(O)NRaRb wherein Ra and Rb are each independently hydrogen, alkyl or any other suitable substituent.
The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to xe2x80x94C(O)Oxe2x80x94.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to RcOxe2x80x94RdOxe2x80x94 wherein Rc is lower alkyl as defined above and Rd is alkylene wherein alkylene is xe2x80x94(CH2)nxe2x80x2,xe2x80x94 wherein nxe2x80x2 is an integer from 1 to 6. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy among others.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to RcNHxe2x80x94 wherein Re is a lower alkyl group, for example, ethylamino, butylamino, among others.
The term xe2x80x9calkenylaminoxe2x80x9d as used herein, alone or in combination, refers to a radical of formula alkenyl-NHxe2x80x94 or (alkenyl)2Nxe2x80x94, wherein the term xe2x80x9calkenylxe2x80x9d is as defined above, provided that the radical is not an enamine. An example of such alkenylamino radical is the allylamino radical.
The term xe2x80x9calkynylaminoxe2x80x9d as used herein, alone or in combination, refers to a radical of formula alkynyl-NHxe2x80x94 or (alkynyl)2Nxe2x80x94 wherein the term xe2x80x9calkynylxe2x80x9d is as defined above, provided that the radical is not an amine. An example of such alkynylamino radicals is the propargyl amino radical.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to RfRgNxe2x80x94 wherein Rf and Rg are independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.
The term xe2x80x9carylxe2x80x9d or xe2x80x9caromaticxe2x80x9d as used herein alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group which is an aromatic ring containing at least one endocyclic N, O or S atom such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. xe2x80x9cAralkylxe2x80x9d and xe2x80x9calkylarylxe2x80x9d employ the term xe2x80x9calkylxe2x80x9d as defined above. Rings may be multiply substituted.
The term xe2x80x9caralkylxe2x80x9d as used herein, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmetbyl, thienylpropyl and the like.
The term xe2x80x9caralkenylxe2x80x9d as used herein, alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms xe2x80x9carylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are as defined above.
The term xe2x80x9carylaminoxe2x80x9d as used herein, alone or in combination, refers to a radical of formula aryl-NHxe2x80x94, wherein xe2x80x9carylxe2x80x9d is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, 2-, 3-, and 4-pyridylamino and the like.
The term xe2x80x9cbenzylxe2x80x9d as used herein, alone or in combination, refers to C6H5xe2x80x94CH2xe2x80x94.
The term xe2x80x9cbiarylxe2x80x9d as used herein, alone or in combination, refers to a radical of formula aryl-aryl, wherein the term xe2x80x9carylxe2x80x9d is as defined above.
The term xe2x80x9cthioarylxe2x80x9d as used herein, alone or in combination, refers to a radical of formula aryl-Sxe2x80x94, wherein the term xe2x80x9carylxe2x80x9d is as defined above. An example of a thioaryl radical is the thiophenyl radical.
The term xe2x80x9caroylxe2x80x9d as used herein, alone or in combination, refers to a radical of formula aryl-COxe2x80x94, wherein the term xe2x80x9carylxe2x80x9d is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein, alone or in combination, refers to a non-aromatic 3- to 10- membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused. The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
The term xe2x80x9calkylheterocyclylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group, including but not limited to 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thiophenyl.
The term xe2x80x9cheterocyclylalkylxe2x80x9d as used herein refers to a heterocyclyl group as previously defined appended to the parent molecular moiety through an alkyl group, including but not limited to 2-thienylmethyl, 2-pyridinylmethyl and 2-(1-piperidinyl) ethyl.
The term xe2x80x9caminalxe2x80x9d as used herein refers to a hemi-acetal of the structure RhC(NRiRj)(NRkRl)xe2x80x94 wherein Rh, Ri, Rj, Rk and Rl are each independently hydrogen, alkyl or any other suitable substituent.
The term xe2x80x9cesterxe2x80x9d as used herein refers to xe2x80x94C(O)Rm, wherein Rm is hydrogen, alkyl or any other suitable substituent.
The term xe2x80x9ccarbamatexe2x80x9d as used herein refers to compounds based on carbamic acid NH2C(O)OH.
The term xe2x80x9coptical isomersxe2x80x9d as used herein refers to compounds which differ only in the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.
Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of xe2x80x94Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94S(O)Oxe2x80x94. Rings may be substituted multiple times.
The terms xe2x80x9celectron-witbdrawingxe2x80x9d or xe2x80x9celectron-donatingxe2x80x9d refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference. Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl and aryl lower alkanoyl among others. Electron sulfonyl donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.
The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, alkyldithio, carboxy lower alkyl, arylalkoxy, alkanoylamino, alkanoyl(lower alkyl)amino, lower alkylsufonylamino, arylsulfonylamino, alkylsulfonyl(lower alkyl)amino, arylsulfonyl(lower alkyl)amino, lower alkylcarboxamide, di(lower alkyl)carboxamide, sulfonamide, lower alkylsulfonamide, di(lower alkyl)sulfonamide, lower alkylsulfonyl, and arylsulfonyl.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
The ring including Y in Formula II or ring Q in Formulae I and V can be a mono-cyclic heterocycle or aromatic ring, or can be a bicyclic ring. When more than one Y is C(R2)(R3), the C substituents from each Y may be joined to form a ring. Moreover, in the rings including Y, two independent R2, R3, R5 and R7 groups taken together may be linked to form a ring.
Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclyl groups or ring including Y defined above, when present, include alcohols, amines, heteroatoms, or any combination of aryl, alkyl, cycloalkyl or heterocyclyl groups either attached directly, or via suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of C, Cxe2x95x90O, CO2, O, N, S, Sxe2x95x90O, SO2, as for example ethers, amides, amines, ureas, sulfamides, sulfonamides, and the like.
In the Formulae I and III-V, defined R groups R1 and R17 potentially substitute their associated rings a number of times. For R1, when q is zero, the associated ring is unsubstituted, having hydrogens at each available position. Similarly, for R17, when s is zero, the associated ring is unsubstituted, having hydrogens at each available position.
For example, R1, R2, R3, R5, R7, R11 and R13 in Formulae I-V above may independently be, but are not limited to, phenyl, thienylmethyl, isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophen-2-yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, 4-((2-toluidinocarbonyl)amino)benzyl, 2-pyridinylethyl, 2-(1H-indol-3-yl)ethyl, 1H-benzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4-(acetylamino)phenyl, 4-methoxyphenyl, 4-aminophenyl, 4-chlorophenyl, (4-(benzylsulfonyl)amino)phenyl, (4-(methylsulfonyl)amino)phenyl, 2-aminophenyl, 2-methylphenyl, isopropyl, 2-oxo-1-pyrrolidinyl, 3-(methylsulfanyl)propyl, (propylsulfanyl)methyl, octylsulfanylmethyl, 3-aminophenyl, 4-((2-toluidinocarbonyl)amino)phenyl, 2-((methylbenzyl)arnino)benzyl, methylsulfanylethyl, ethylsulfanylmethyl, 2-chlorobenzyl, 2-bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4-dichlorobenzyl, 2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chloro-5-(trifluoromethyl)benzyl, 2-chloro-6-methylbenzyl, 2,6-dimethoxybenzyl, 2-chloro-5-(methylsulfonyl)benzyl, 2-chloro-6-cyanobenzyl, 2-chloro-6-ethoxybenzyl, 2-chloro-5-methoxybenzyl, 2-chloro-5-fluorobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclopropyl, tert-butylamino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl, 4-morpholino, (4-carboxyphenyl)amino, pivaloylamino, ((tert-butylamino)carbonyl)amino, trifluoromethyl, benzyloxy, 2-(2-metboxyethoxy)ethoxy, 2-(2-(2-methoxyethoxy)ethoxy)ethoxy and 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy. R6 and R8 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-piperidinyl, and 4-tetrahydropyranyl among others. R4 and R13 may be linked to form a ring such as pyrrolidino, 1-piperidino, 4-methyl-1-piperazino, 4-aceto-1-piperazino, and 4-morpholino among others. R9 and R10 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl among others.
The R4 substituent for Formulae I-III and the R21 substituent of Formula IV above may be, but are not limited to, 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl,methysulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4,5-dihydro-1,3-oxazol-2-yl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 7-methoxy-1,3-benzodioxol-5-yl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3-ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy-4-methylphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 3-(2-methoxyethoxy)phenyl, 3,4-dipropoxyphenyl, 3-(difluoromethoxy)phenyl, 2-naphthyl, 3-isopropoxyphenyl, 1-methyl-1H-indol-5-yl, 2,3-dihydro-1-benzofuran-5-yl, 1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 3-(trifluoromethoxy)phenyl, 1-methyl-1H-indol-6-yl, 3-(cyclopropoxy)phenyl, 3-(cyclopropylmethoxy)phenyl, 3-(difluoromethoxy)phenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl, 1-ethyl-1H-indol-5-yl, 3-(diethylamino)phenyl, 6-methoxy-2-naphthyl, 3-[(methylsulfonyl)amino]phenyl, 3-[methyl(methylsulfonyl)amino]phenyl, 3-[ethyl(methylsulfonyl)amino]phenyl, 1H-indol-5-yl, 3-fluoro-4-methoxyphenyl, and 3-(difluoromethyl)phenyl.
The R6 and R8 substituents for Formulae I-V above may be, but are not limited to hydrogen, butyl, benzyl, benzyloxymethyl, ethyl, propyl, phenylsulfanylmethyl, benzylsulfanylmethyl, methylsulfanylethyl, ethylsulfanylmethyl, methyl, or carboxyethyl.
R4 and R13 may be linked to form a ring such as 1-pyrrolidino, 1-piperidino, 4-methyl-1-piperazino, 4-acetyl-1-piperazino and 4-morpholino among others.
R6 and R8 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, among others.
R9 and R10 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, among others.
Abbreviations which have been used in the schemes and the examples which follow are: BOC for t-butyloxycarbonyl; EtOAc for ethyl acetate; DMF for dimethylformamide; THF for tetrahydrofuran; Tos for p-toluenesulfonyl; DCC for dicyclohexylcarbodiimide; HOBT for 1-hydroxybenzotriazole; TFAA for trifluoroacetic anhydride; NMM for N-methyl morpholine; DIPEA for diisopropylethylamine; DCM for methylene dichloride; LHMDS for lithium hexamethyl disilazide; NaHMDS for sodium hexamethyl disilazide; CDI for 1,1xe2x80x2-carbonlyldiimidazole HBTU for O-benzotriazol-1-yl-N,N,Nxe2x80x2, Nxe2x80x2-tetramethyluronium hexafluorophosphate, EDCI for 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride and TBS for TRIS-buffered saline. Amino acids are abbreviated as follows: C for L-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; I for L-isoleucine; L for L-leucine; N for L-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T for L-threonine; V for L-valine, and W for L-tryptophan.